Management of Dyslipidemia in Adults With Diabetes:
A Report from the ADA in 2004 and NCEP-ATP-III
Introduction :
Type 2 diabetes is associated with a
two- to fourfold excess risk of coronary heart disease (CHD).
Although the degree of glycemia in diabetic patients is strongly
related to the risk of microvascular complications, the relation of
glycemia to macrovascular disease in type 2 diabetes is more modest.
The finding of increased cardiovascular risk factors before the
onset of type 2 diabetes suggests that a multifactorial approach to prevention
of CHD in type 2 diabetes will be necessary.
Dyslipidemia and type 2 diabetes :
The most common pattern of dyslipidemia
in type 2 diabetic patients is elevated triglyceride levels and
decreased HDL cholesterol levels. The concentration of LDL
cholesterol in type 2 diabetic patients is usually not significantly
different from nondiabetic individuals. However, type 2 diabetic
patients typically have a preponderance of smaller, denser LDL
particles, which possibly increases atherogenicity even if the
absolute concentration of LDL cholesterol is not significantly
increased.
Lipoprotein risk factors for CHD :
Baseline data from the
United Kingdom Prospective Diabetes Study (UKPDS) showed that both
decreased HDL and elevated LDL predicted CHD. In observational
studies, HDL may be the most consistent predictor of CHD in type 2
diabetes subjects, followed by triglyceride and total cholesterol.
Clinical trials of lipid lowering in diabetic subjects :
The recently completed Heart Protection Study is the largest study to date which showed that diabetic patients assigned to simvastatin had a 22% reduction in the event rate for major CVD events, regardless of what the initial LDL-C level was. Numerous other statin trials have included much smaller numbers of adult type 2 diabetic subjects but have shown similar reductions in CVD events too. In the Scandinavian Simvastatin Survival Study (4S) trial, simvastatin (HMG CoA reductase inhibitor) significantly reduced CHD incidence and total mortality (borderline significantly) in diabetic subjects with high LDL cholesterol and with previous clinical CHD. In the Cholesterol and Recurrent Events (CARE) study, pravastatin reduced CHD incidence significantly in diabetic subjects with average LDL levels and with previous clinical CHD. In the Helsinki Heart Study, gemfibrozil (fibric acid derivative) was associated with a reduction in CHD in diabetic subjects without prior CHD (although this result was not statistically significant). In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), gemfibrozil was associated with a 24% decrease in cardiovascular events in diabetic subjects with prior cardiovascular disease.
Modification of lipoproteins by
medical nutrition therapy and physical activity:
The ADA has made recommendations for both medical nutrition therapy (MNT) and physical activity. Weight loss and increased physical activity will lead to decreased triglyceride and increased HDL cholesterol levels and also to modest lowering of LDL cholesterol levels. Diabetic patients who are overweight should be given a prescription for MNT and for increased physical activity. The proportion of saturated fat in the meal plan should be reduced. The ADA suggests an increase in either carbohydrate or monounsaturated fat to compensate for the reduction in saturated fat. Some (but not all) studies suggest that a high–monounsaturated fat diet may have better metabolic effects than a high-carbohydrate diet, although other experts have suggested that such a dietary modification may make weight loss more difficult in obese diabetic patients.
Modification of lipoproteins by glucose-lowering agents:
Optimal glycemia control usually lower triglyceride and may also lower LDL cholesterol levels. Since improved glycemic control lower triglyceride levels, it might also cause a favorable change in LDL composition. Although in general glucose-lowering agents do not change or have only a modest effect on raising HDL levels, the HDL composition may change in a direction thought to be antiatherogenic. Thiazolidinediones may increase HDL and LDL levels, but the long-term effect of such changes is not known.
Treatment goals for lipoprotein therapy:
Optimal LDL cholesterol levels for adults with diabetes are <100 mg/dl, optimal HDL cholesterol levels are >40 mg/dl (or >50 mg/dl in women), and desirable triglyceride levels are <150 mg/dl. These recommendations are based not only on the high incidence of CHD in patients with diabetes, but also on their higher case fatality rate once they have CHD.
Order of priorities for treatment of
diabetic dyslipidemia:
Treatment
of LDL cholesterol is considered as the first priority for
pharmacological therapy of diabetic dyslipidemia for a number of reasons.
Clinical trials (4S and CARE) showing the effectiveness of statins
in reducing CHD in diabetic subjects show greater risk reductions
with narrower confidence intervals than the Helsinki Study with
gemfibrozil. Since diabetes is designated a CHD risk equivalent in NCEP
ATP-III, the LDL cholesterol goal of therapy for patients with diabetes should
be < 100 mg/dl. Hence if diabetic subjects with clinical CVD and an LDL
cholesterol level of 
100 mg/dl after MNT and glucose
interventions, they should be treated with pharmacological agents
(statin as first choice). For diabetic patients without preexisting CVD,
the current ADA recommendations for starting pharmacological therapy
are an LDL cholesterol level of 130 mg/dl and a goal of <100 mg/dl for LDL
cholesterol. Furthermore, as improvement of glycemic control will
only modestly reduce LDL cholesterol levels, diabetic patients with
both high LDL cholesterol and high glucose levels might simultaneously
be initiated with glucose lowering and LDL-lowering therapy. For example, when
LDL cholesterol is ³ 130
mg/dl, most persons with diabetes will require initiation of LDL-lowering drugs
(statins preferred) simultaneously with therapeutic lifestyle changes (TLC) to
achieve the LDL goal. When LDL cholesterol levels are in the range of 100-129
mg/dl at baseline or on treatment, several therapeutic options are available:
more aggressive MNT, intensifying control of other risk factors including
hyperglycemia, adding a drug to modify atherogenic dyslipidemia (fibrate such
as fenofibrate, or nicotinic acid, the former preferred, for diabetic patients
with HDL <40 mg/dl, or statin if HDL >40 mg/dl). Raising HDL cholesterol
levels pharmacologically in diabetic patients is very difficult since
the most effective agent raising HDL cholesterol levels is nicotinic
acid, which is relatively contraindicated in diabetic patients.
However, fibrates can raise HDL cholesterol levels significantly without
affecting glycemic control. In older persons (³65 years of age) with diabetes but no additional CHD risk factors
other than age, clinical judgment is required for how intensively to apply
these guidelines;a variety of factors, including concomitant illnesses, general
health status, and social issues may influence treatment decisions and may
suggest a more conservative approach.
The treatment strategy for elevated triglycerides depends on the causes of the elevation and its severity. The primary aim of therapy for diabetic dyslipidemia is to achieve the target goal for LDL cholesterol as mentioned above. According to NCEP-ATP-III, when triglycerides are borderline high (150-199 mg/dl), the initial therapy for hypertriglyceridemia is behavioral modification with weight loss, increased physical activity, and moderation of alcohol consumption. Improved glycemic control is also very effective for reducing triglyceride levels and should be aggressively used before the introduction of drug therapy. When triglyceride levels are ³200 mg/dl~499 mg/dl, non-HDL cholesterol(LDL+VLDL, or T.C-HDL) becomes a secondary target of cholesterol-lowering therapy and the goal for non-HDL cholesterol can be set at 30 mg/dl higher than that for LDL cholesterol on the premise that a VLDL cholesterol level £ 30 mg/dl is normal. There are two approaches to triglyceride-lowering drug therapy. First the non-HDL cholesterol goal can be achieved by intensifying therapy with an LDL-lowering drug (statin); or second, fibrate (preferred) or nicotinic acid can be added, if used with appropriate caution, to achieve the non-HDL cholesterol goal by further lowering of VLDL cholesterol. In the case of severe hypertriglyceridemia (≧500 mg/dl ), the initial aim of therapy is to prevent acute pancreatitis through triglyceride lowering. This approach requires very low fat diets (<10%~15% of calorie intake), weight reduction, increased physical activity, in addition to simultaneous fibric acid therapy. Only after triglyceride levels have been lowered to < 500 mg/dl should attention turn to LDL lowering to reduce risk for CHD.
In some
cases, combined lipid therapy may be initiated. The combination of
statins with nicotinic acid is extremely effective in modifying diabetic
dyslipidemia (with the largest increases in HDL cholesterol levels),
but the combination may significantly worsen hyperglycemia. Thus,
this combination should be used with extreme caution: use low doses
of nicotinic acid (
2 g of nicotinic acid per day) with
frequent monitoring of glucose levels. It should also be noted that the
combination of statins with nicotinic acid and especially with
fibrates has been associated with increased risk of myositis,
although the risk of clinical myositis (as opposed to elevated
creatinine phosphokinase levels) appears to be low (except in case
of renal failure). Furthermore, it should be noted that either gemfibrozil or
bezafibrate should not be initiated alone in diabetic patients who
have undesirable levels of both triglyceride and LDL cholesterols
due to their relatively low or even worse LDL-lowering effects. However
fenofibrate, a recently approved fibric acid derivative that has
greater LDL-lowering effects as well as greater HDL-elevating effect, may be
initiated singly in patients with diabetic dyslipidemia.
Choice of lipid-lowering agents:
Generally, one or two agents
are available in each class with the exception of the statins, for
which there are many. The choice of statin should depend principally
on the LDL reduction needed to achieve the target (<100 mg/dl),
on the initial LDL level, and on the judgment of the treating
physician. It should also be noted that the higher doses of statins may be
moderately effective at reducing triglyceride levels (though not
necessarily at raising HDL levels) and thus may reduce the need for
combination therapy. However, with the use of high doses of statins,
the LDL levels may be reduced to 80 mg/dl or less, and there is no
safety data at such low LDL levels. Hence the use of very high-dose
statin therapy (i.e., simvastatin 80 mg or atorvastatin 40 or 80 mg)
to treat hypertriglyceridemia should be restricted to patients with
both high levels of LDL cholesterol as well as high triglyceride
levels. Changes in therapy should be done at 4- to 6-week intervals based on
laboratory findings.
Considerations in the treatment of adults with type 1 diabetes:
Type 1 diabetic patients who are in good control tend to have normal levels of lipoprotein. Their composition of lipoproteins may be abnormal, but the effects of these compositional abnormalities in relation to CHD are unknown. There is relatively little observational data on lipoproteins and CHD, and there are no clinical trials relating lipoproteins to CHD. It seems reasonable that if type 1 diabetic patients have LDL cholesterol levels that are above the goals recommended for type 2 diabetic patients, they should be aggressively treated. In addition, improved glycemic control may be even more important in type 1 diabetic patients than in type 2 diabetic patients for reduction of CHD (e.g., Wisconsin Epidemiologic Study of Diabetic Retinopathy [WESDR]).
References:
1. Dyslipidemia Management in Adults With Diabetes. American Diabetes Association Position statement. Diabetes Care 2004;27(Suppl 1):S68-S71.
2. Heart Protection Study Collaborative Group:MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes:a randomized placebo-controlled trial. Lancet 2003;361:2005-16.
3. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
4. American Diabetes Association: Detection and management of lipid disorders in diabetes (Consensus Statement). Diabetes Care 1993;16:828–834.
5. Haffner SM: Management of dyslipidemia in adults with diabetes (Technical Review). Diabetes Care 1998;21:160–178 (Recent revision:2000).
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